Aneurysms are focal dilatations in blood vessels estimated to account for 1-2% of all deaths in industrialized countries. No effective pharmacological therapies exist to prevent rupture, and the only treatment option is prophylactic surgical repair. The study of monogenic diseases that carry a high risk for aneurysm has identified critical components in pathogenesis, including signaling pathways that regulate development and homeostasis of vascular cells, and proteins that regulate the assembly and function of the extracellular matrix. In two hereditary aneurysm disorders, Loeys-Dietz Syndrome (LDS) and autosomal recessive cutis laxa type 1B (ARCL1B), excessive activation of the angiotensin II (AngII) receptor I (AT1R) signaling pathway has been identified as the common downstream driver of aneurysm. LDS is caused by mutations that impair but don't completely abolish transforming growth factor-? (TGF-?) signaling; ARCL1B is caused by homozygous loss-of- function mutations in the extracellular matrix protein fibulin-4 (EFEMP2/FBLN4). Although these conditions are caused by mutations in ubiquitously expressed genes, disease predominantly develops in the aortic root in LDS and in the more distal ascending aorta in ARCL1B. No molecular explanation exists for this regional predisposition. A molecular understanding of the processes that predispose or protect certain regions from aneurysm may lead to the development of therapies that specifically target these mechanistic vulnerabilities. Our previous work indicates that the embryological origin of second heart field (SHF)-derived smooth muscle cells, found predominantly in the aortic root, and cardiac neural crest (CNC)-derived smooth muscle cells, found predominantly in the ascending aorta, defines the intrinsic vulnerability of these cells to the effects of an LDS-causing mutation. Using mouse models of LDS and ARCL1B, we will test the central hypothesis that local risk of dilation is driven by critical gene-by-lineage interactions that perturb processes that, in healthy individuals, physiologically suppress AT1R signaling in smooth muscle cells. We will use a combination of novel in vivo approaches and epigenetic and transcriptional analyses to accomplish the following aims. In Aim 1, we will interrogate whether and how the timing of partial TGF-? signaling loss affects aneurysm development and sensitization to AT1R signaling. In Aim 2, we will examine the pathogenic role and mechanisms of lineage-specific AT1R signaling enhancement in a mouse model of LDS. In Aim 3, we will use a mouse model of ARCL1B to examine if and how the embryological origin of smooth muscle cells modifies the signaling and transcriptional consequences associated with fibulin-4 deficiency. Understanding the mechanisms that predispose certain arterial regions to disease has the potential to uncover fundamental aspects of vascular biology, and inform the development of new therapies. Our experience in the analysis of lineage-specific events in a mouse model of LDS, our preliminary data, and strong collaborative team with the necessary computational skills make us uniquely positioned to conduct these studies.